PROJECT SUMMARY Restoration and optimization of cerebral blood flow (CBF) are the cornerstones of acute stroke management, but evidence suggests substantial hemodynamic variability between patients. Over the last few years, mechanical thrombectomy has revolutionized treatment for acute stroke with large vessel occlusion. With this procedure, clot is endovascularly removed to achieve large artery recanalization in the majority of patients. Unfortunately, microvascular hypoperfusion can persist despite large vessel recanalization, and microvascular flow status is a better predictor of infarct volume and clinical outcome than large artery recanalization. This proposal seeks to apply novel methods, most notable diffuse correlation spectroscopy, for noninvasive assessment of cerebral microvascular hemodynamics during mechanical thrombectomy. This work will identify individual variability in microvascular reperfusion. Impaired autoregulation is known to occur in acute stroke, and provides the rationale for liberalization of blood pressure targets. DCS data will also be used for bedside measurement of individual variations in cerebral autoregulation based on dynamic correlations between arterial blood pressure and CBF. Finally, structural and perfusion MRI will be used to assess imaging outcomes, and for validation of optical CBF measurements. This project will define the incidence and clinical significance of persistent microvascular hypoperfusion and autoregulatory dysfunction after thrombectomy, which in future work will serve as novel therapeutic targets to individualize stroke treatment and further improve clinical outcomes. The proposed work will also provide critical career development for the candidate?s growth towards independence, with expertise in measuring cerebral hemodynamics and penumbral physiology in acute stroke. This proposal builds upon the candidate?s foundation in optical blood flow monitoring, expanding its application to a high-acuity setting, leveraging the technology?s advantage as a non-invasive bedside tool. Training in advanced MRI as a complementary tool for assessing cerebral hemodynamics with high spatial resolution will diversify the candidate?s expertise. The proposal will also provide training in advanced biostatistics, study methodology, and rigor. Mentorship, critical to the candidate?s success, will be provided by an experienced interdisciplinary team of senior faculty with a track record of success in training independent researchers. The team is led by: (1) primary mentor Dr. John Detre, a world renowned expert in neuroimaging, who has been critical in the development of optical and MRI methods utilized in this proposal, (2) Dr. Scott Kasner, an internationally distinguished stroke clinical trialist, and (3) Dr. Arjun Yodh, an internationally renowned investigator in biomedical optics and developer of the technology used in this work. These mentors will ensure the proposed research and training plan guide the candidate in establishing an independent research program in non-invasive cerebral hemodynamic monitoring.